Flash Photodynamic Therapy – How the Saturation of Photosensitizer Absorption Enables Selective and Deeper Tumor Treatments

FLASH‐PDT uses strongly‐absorbing photosensitizers and pulsed lasers to saturate the photosensitizer absorption at ≈1‐cm tissue depths. This allows for the generation of [ROS] above the necrosis threshold level for tumors, while maintaining [ROS] in peritumoral tissues below that threshold, even when the tumor‐to‐peritumoral tissue ratio is as low as 2. The result is selective and in‐depth tumor treatment. Abstract FLASH therapies are attracting tremendous interest because they spare normal tissues while maintaining tumor‐destroying efficacy, when compared with continuous delivery of radiation. In Photodynamic Therapy (PDT), it has been noted that continuous‐wave and pulsed lasers give comparable results for a variety of tumors, but the conditions for increased tumor‐to‐peritumoral tissue selectivity have never been reported. This work presents a model that explains how pulsed lasers, in combination with photosensitizers, can offer selective and in‐depth tumor ablation. It is shown that the photosensitizer absorption must be saturated to obtain the FLASH effect. The importance of the number of laser pulses to destroy tumor tissue and spare normal tissue is demonstrated. The predictions of the model and the superiority of FLASH‐PDT are validated with the treatment of subcutaneous CT26 and orthotopic 4T1 tumors models. Notably, FLASH‐PDT with redaporfin significantly increases the overall survival of mice with 4 mm orthotopic 4T1 tumors and lung metastasis. FLASH‐PDT allows for the use of order‐of‐magnitude higher drug or light doses without affecting healthy tissues, while promoting selective and deeper tumor treatments. FLASH-PDT uses strongly-absorbing photosensitizers and pulsed lasers to saturate the photosensitizer absorption at ≈1-cm tissue depths. This allows for the generation of [ROS] above the necrosis threshold level for tumors, while maintaining [ROS] in peritumoral tissues below that threshold, even when the tumor-to-peritumoral tissue ratio is as low as 2. The result is selective and in-depth tumor treatment. Abstract FLASH therapies are attracting tremendous interest because they spare normal tissues while maintaining tumor-destroying efficacy, when compared with continuous delivery of radiation. In Photodynamic Therapy (PDT), it has been noted that continuous-wave and pulsed lasers give comparable results for a variety of tumors, but the conditions for increased tumor-to-peritumoral tissue selectivity have never been reported. This work presents a model that explains how pulsed lasers, in combination with photosensitizers, can offer selective and in-depth tumor ablation. It is shown that the photosensitizer absorption must be saturated to obtain the FLASH effect. The importance of the number of laser pulses to destroy tumor tissue and spare normal tissue is demonstrated. The predictions of the model and the superiority of FLASH-PDT are validated with the treatment of subcutaneous CT26 and orthotopic 4T1 tumors models. Notably, FLASH-PDT with redaporfin significantly increases the overall survival of mice with 4 mm orthotopic 4T1 tumors and lung metastasis. FLASH-PDT allows for the use of order-of-magnitude higher drug or light doses without affecting healthy tissues, while promoting selective and deeper tumor treatments. Advanced Science, EarlyView.